Helper T cells are divided into Th1 cells and Th2 cells based on the cytokines they produce. The Th1 cells produce cytokines such as interleukin-2 (hereinafter IL-2), interferon-.gamma. (hereinafter IFN-.gamma.) and the like and mainly regulate cellular immunity. The Th2 cells produce cytokines such as IL-4, IL-5, interleukin-10 (hereinafter IL-10) and the like and mainly regulate humoral immunity. Immune responses are regulated on the balance between the Th1 cells and Th2 cells. The IFN-.gamma. produced by Th1 cells promotes differentiation into Th1 cells but inhibits differentiation into Th2 cells. The IL-4 produced by Th2 cells promotes differentiation into Th2 cells but inhibits differentiation into Th1 cells.
In recent years, the onset of various immune diseases has been clarified to be triggered by a failure to balance Th1 cells and Th2 cells. Reports have been documented that Th2 cells are dominant in allergic diseases and systemic autoimmune diseases and Th1 cells are dominant in organ-specific autoimmune diseases. of the cytokines produced by Th2 cells, IL-4 shows class switching to immunoglobulin E (IgE) and induction of differentiation into Th2 cells, and IL-5 shows activation of eosinophil and induction of infiltration, and is involved particularly deeply in the formation of an allergic disease state. In fact, many studies have reported that large amounts of IL-4 and IL-5 were found in bronchoalveolar lavage fluid of patients with asthma and mRNAs of IL-4 and IL-5 were found in rash from patients with atopic dermatitis (Am. J. Respir. Cell Mol. Biol., Vol. 12, pp.477-487, 1995, J. Immunol., Vol. 158, pp. 3539-3544 and J. Exp. Med., Vol. 173, pp. 775-778, 1991).
Also, there is a report that various allergic reactions are less easily induced in mice defective in IL-4 or IL-5 gene (Nature, Vol. 362, pp. 245-247, 1993 and J. Exp. Med., Vol. 183, pp. 195-201, 1996). In addition, infiltration of eosinophils could be reportedly inhibited strongly by the administration of an anti-IL-5 antibody in various animal models inclusive of airway inflammation model monkey (Am. J. Respir. Crit. Care Med., Vol. 152, pp. 467-472, 1995).
It has been elucidated using animal models of allergic diseases that IL-4 or IL-5 is involved in the onset of these diseases.
Therefore, a pharmaceutical agent that inhibits production of IL-4 and IL-5 in allergic patients, that improves a shift toward Th2 cells and that inhibits eosinophilic inflammation is considered to make a useful anti-allergy drug.
While JP-B-7-53716 discloses a certain imidazole derivative having an antiphlogistic effect and analgesic effect, but this publication is silent on an inhibitory effect and the like on the production of IL-4 or IL-5 by Th2 cells.
With regard to suplatast tosilate (IPD-1151T) recently developed, a clinical achievement report has been documented that it has a specific inhibitory effect on the production of IL-4 and IL-5 by Th2 cells, and is effective against asthma and atopic dermatitis (Journal of Clinical Therapeutics & Medicines, Vol. 8, No. 7, 1992). However, the inhibitory effect provided by IPD-1151T on the production of IL-4 and IL-5 is not very potent, and it is not clear if a clinical dose is sufficient to express an inhibitory effect on the production of IL-4 and IL-5.
At present, steroidal agents have been widely used for the treatment of allergic diseases and show high clinical effects. Steroidal agents exhibit an IL-5 production inhibitory effect among the broad range of effects, and the IL-5 production inhibitory effect is considered to be the mechanism of inhibition of eosinophilic inflammation. Due to the broad range of effects provided by steroidal agents, however, side effects pose serious problems.
Recent reports show that immunosuppressants such as cyclosporin A and tacrolimus also inhibit production of IL-5, and are effective against eosinophilic inflammation. These drugs, nevertheless, are associated with side effects to kidney, side effects of immunosuppression, induction of infections and the like, due to the wide inhibition they provide with respect to the production of cytokines of not only IL-5 but also IL-2.
Therefore, creation of a therapeutic agent for allergic diseases having an equally potent anti-allergic action as steroidal agents and causing less side effects is awaited.
A compound having a specific IL-4 and IL-5 production inhibitory effect is expected to make a pharmaceutical agent with less side effect as compared to conventional drugs and to be useful for the prophylaxis and treatment of allergic diseases such as atopic dermatitis, bronchial asthma and allergic rhinitis, because it improves the shift toward Th2 cells and suppresses eosinophilic inflammation in allergic patients.
It is therefore an object of the present invention to provide a drug that specifically inhibits production of particularly IL-4 and IL-5 that are deeply involved in the formation of a disease state of allergy, from among the cytokines produced by Th2 cells.